Structure−Activity Relationships in 1,4-Benzodioxan-Related Compounds. 6. Role of the Dioxane Unit on Selectivity for α1-Adrenoreceptor Subtypes

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Abstract
WB 4101-related benzodioxans 3−9 were synthesized, and their biological profiles at α1-adrenoreceptor subtypes and 5-HT1A serotoninergic receptors were assessed by binding assays in CHO and HeLa cells membranes expressing the human cloned receptors. Furthermore, receptor selectivity of selected benzodioxan derivatives was further determined in functional experiments in isolated rat vas deferens (α1A) and aorta (α1D) and guinea pig spleen (α1B), in additional receptor binding assays in rat cortex membranes containing α2-adrenoreceptors and 5-HT2 serotoninergic receptors, and in rat striatum membranes containing D2 dopaminergic receptors. An analysis of the results of receptor binding experiments for benzodioxan-modified derivatives 3−9 showed high affinity and selectivity toward the α1a-adrenoreceptor subtype for compounds 3−5 and 7 and a reversed selectivity profile for 9, which was a selective α1d antagonist. Furthermore, the majority of structural modifications performed on the prototype 1 (WB 4101) led to a marked decrease in the affinity for 5-HT1A serotoninergic receptors, which may have relevance in the design of selective α1A-adrenoreceptor antagonists. The exception to these findings was the chromene derivative 8, which exhibited a 5-HT1A partial agonist profile.

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